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Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells.

Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, Raymond E - Br. J. Cancer (2008)

Bottom Line: The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent.In addition, PEP005 increased the phosphorylation of PKC delta and p38.In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects.

View Article: PubMed Central - PubMed

Affiliation: INSERM U728, RayLab, Department of Medical Oncology, Beaujon University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc, Clichy 92110, France.

ABSTRACT
PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC(50) of PEP005 ranged from 0.01-140 microM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

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Chemical structure of PEP005 and phorbol 12-myristate 13-acetate (PMA).
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fig1: Chemical structure of PEP005 and phorbol 12-myristate 13-acetate (PMA).

Mentions: PEP005 is a novel ingenol angelate extracted and purified from Euphorbia peplus. Chemically, PEP005 is structurally analogous to phorbol esters (Figure 1) and is a potent modulator of PKC isoenzymes (Kedei et al, 2004). PEP005 is currently being developed as a topical treatment for actinic keratoses and basal cell carcinoma (www.cancertrials.gov). In earlier studies, PEP005 was shown to modulate PKCs by activating PKCδ in human myeloid leukaemia cancer cell lines, thereby inducing cellular apoptosis (Hampson et al, 2005) in melanoma models, inducing senescence through PKC-mediated activation of the MAPK pathway (Cozzi et al, 2006) and in colon cancer models, inducing apoptosis through the inhibition of the AKT signalling pathway (Serova et al., 2008). PEP005 appears to be selective for growth inhibition of cancer cells as it does not inhibit the growth of human neonatal fibroblasts (Cozzi et al, 2006) and does not induce apoptosis in normal CD34+ cord blood myeloblasts (Hampson et al, 2005). In leukaemia cells, resistance to PEP005 was associated with the failure to express PKCδ. In solid tumours, PEP005 was shown to induce necrosis in human melanoma, cervical cancer, and prostate xenografts (Ogbourne et al, 2004).


Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells.

Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, Raymond E - Br. J. Cancer (2008)

Chemical structure of PEP005 and phorbol 12-myristate 13-acetate (PMA).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600681&req=5

fig1: Chemical structure of PEP005 and phorbol 12-myristate 13-acetate (PMA).
Mentions: PEP005 is a novel ingenol angelate extracted and purified from Euphorbia peplus. Chemically, PEP005 is structurally analogous to phorbol esters (Figure 1) and is a potent modulator of PKC isoenzymes (Kedei et al, 2004). PEP005 is currently being developed as a topical treatment for actinic keratoses and basal cell carcinoma (www.cancertrials.gov). In earlier studies, PEP005 was shown to modulate PKCs by activating PKCδ in human myeloid leukaemia cancer cell lines, thereby inducing cellular apoptosis (Hampson et al, 2005) in melanoma models, inducing senescence through PKC-mediated activation of the MAPK pathway (Cozzi et al, 2006) and in colon cancer models, inducing apoptosis through the inhibition of the AKT signalling pathway (Serova et al., 2008). PEP005 appears to be selective for growth inhibition of cancer cells as it does not inhibit the growth of human neonatal fibroblasts (Cozzi et al, 2006) and does not induce apoptosis in normal CD34+ cord blood myeloblasts (Hampson et al, 2005). In leukaemia cells, resistance to PEP005 was associated with the failure to express PKCδ. In solid tumours, PEP005 was shown to induce necrosis in human melanoma, cervical cancer, and prostate xenografts (Ogbourne et al, 2004).

Bottom Line: The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent.In addition, PEP005 increased the phosphorylation of PKC delta and p38.In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects.

View Article: PubMed Central - PubMed

Affiliation: INSERM U728, RayLab, Department of Medical Oncology, Beaujon University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc, Clichy 92110, France.

ABSTRACT
PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC(50) of PEP005 ranged from 0.01-140 microM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

Show MeSH
Related in: MedlinePlus